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- PDB-5vo6: CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN IN COMPLEX WITH A PYRROLO... -

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Basic information

Entry
Database: PDB / ID: 5vo6
TitleCRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN IN COMPLEX WITH A PYRROLOPYRIDAZINE INHIBITOR
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE / TRANSFERASE-INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling ...negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / tyrosine phosphorylation of STAT protein / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / Signaling by ALK / extrinsic component of plasma membrane / Interleukin-20 family signaling / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / B cell differentiation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / RAF/MAP kinase cascade / regulation of apoptotic process / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / intracellular signal transduction / endosome / protein phosphorylation / innate immune response / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak3 / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM domain / FERM domain profile. ...Tyrosine-protein kinase, non-receptor Jak3 / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-9J4 / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsSack, J.S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
Authors: Hynes, J. / Wu, H. / Kempson, J. / Duan, J.J. / Lu, Z. / Jiang, B. / Stachura, S. / Tokarski, J.S. / Sack, J.S. / Khan, J.A. / Lippy, J.S. / Zhang, R.F. / Pitt, S. / Shen, G. / Gillooly, K. ...Authors: Hynes, J. / Wu, H. / Kempson, J. / Duan, J.J. / Lu, Z. / Jiang, B. / Stachura, S. / Tokarski, J.S. / Sack, J.S. / Khan, J.A. / Lippy, J.S. / Zhang, R.F. / Pitt, S. / Shen, G. / Gillooly, K. / McIntyre, K. / Carter, P.H. / Barrish, J.C. / Nadler, S.G. / Salter-Cid, L.M. / Fura, A. / Schieven, G.L. / Pitts, W.J. / Wrobleski, S.T.
History
DepositionMay 2, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2017Group: Database references
Revision 1.2Jun 21, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6312
Polymers33,2541
Non-polymers3771
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.350, 75.040, 86.960
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Tyrosine-protein kinase JAK3 / Janus kinase 3 / JAK-3 / Leukocyte janus kinase / L-JAK


Mass: 33254.016 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN (UNP RESIDUES 810-1100) / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9J4 / 4-{[(1R,3S)-3-amino-2,2,3-trimethylcyclopentyl]amino}-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide


Mass: 377.483 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.32 Å3/Da / Density % sol: 47.05 %
Crystal growTemperature: 300 K / Method: vapor diffusion / Details: NULL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.65→86.96 Å / Num. obs: 9467 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 60.32 Å2 / Rmerge(I) obs: 0.145 / Net I/σ(I): 9.2
Reflection shellResolution: 2.65→2.79 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.813 / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→43.48 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.851 / SU R Cruickshank DPI: 0.938 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.105 / SU Rfree Blow DPI: 0.359 / SU Rfree Cruickshank DPI: 0.36
RfactorNum. reflection% reflectionSelection details
Rfree0.284 765 8.12 %RANDOM
Rwork0.209 ---
obs0.215 9417 99.5 %-
Displacement parametersBiso mean: 45.47 Å2
Baniso -1Baniso -2Baniso -3
1--6.1532 Å20 Å20 Å2
2--1.816 Å20 Å2
3---4.3372 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.65→43.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2121 0 28 17 2166
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012203HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.12991HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d743SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes44HARMONIC2
X-RAY DIFFRACTIONt_gen_planes343HARMONIC5
X-RAY DIFFRACTIONt_it2203HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion19.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion269SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2497SEMIHARMONIC4
LS refinement shellResolution: 2.65→2.96 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2734 210 8.05 %
Rwork0.2065 2398 -
all0.212 2608 -
obs--99.05 %

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